tbuckley/cabot-search huggingface dataset:
Abstract 13301: Rasa3 is a Novel Candidate Gene in Sickle Cell Disease-Associated Pulmonary Hypertension and Pulmonary Arterial Hypertension
Authors: Clare C Prohaska, Xu Zhang, Tae-Hwi Schwantes-An, Robert Stearman, Micheala A Aldred, Katie Lutz, Michael Pauciulo, Bill Nichols, Ankit A Desai, Victor Gordeuk, Roberto F Machado
Journal: Circulation (2022)

Introduction: Pulmonary hypertension (PH) is associated with significant morbidity and mortality. RASA3, a GTPase-activating protein, is integral to processes highly relevant to PH. We explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associated PH and pulmonary arterial hypertension (PAH). Methods: Using peripheral blood mononuclear cells (PBMC) from 3 cohorts of subjects with SCD, cis-expression quantitative trait loci (eQTL) were queried for RASA3 . Genome-wide single nucleotide polymorphisms (SNP) near or in the RASA3 gene that associate with lung RASA3 expression were identified using Genotype Tissue Expression project data, reduced to 9 tagging SNPs for RASA3 and associated with PH markers. Associations between the top RASA3 SNP and PAH severity were tested using whole genome genotype data from PAH Biobank subjects. Using RNAseq samples aligned with SNP arrays from lung tissue from the Pulmonary Hypertension Breakthrough Initiative (PHBI), we evaluated the frequency of the risk allele at our SNP of interest. Results: PBMC RASA3 expression was significantly lower in patients with SCD-associated PH using elevated TRV≥2.5m/s and RHC data and associated with significantly higher mortality. One eQTL for RASA3 was identified, rs9525228, with the risk allele correlating with PH risk and severity in patients with SCD-associated PH. Analyzing this SNP in PAH patients based on either European or African ancestry (EA, AA), we found that rs9525228 associated with markers of PH in EA but not AA individuals (Table 1). There was a trend towards decreased survival in EA individuals carrying rs9525228 (p=0.08) that was not seen among AA individuals. Using PHBI samples, individuals homozygous for the risk allele had lower RASA3 expression (p=0.05). Conclusions: RASA3 is a novel candidate gene in SCD-associated PH and PAH and appears to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.
Abstract 13335: The Predictive Value of Paced Qrs Frequency Analysis in Achieving Left Bundle Branch Pacing
Authors: Ramya Vajapey, Ram Amuthan, Mina K Chung, Patrick Tchou, John Rickard, Roy Chung, Niraj Varma, Mark J Niebauer
Journal: Circulation (2022)

Introduction: Left bundle branch area pacing (LBp) is a newer technique to deliver more synchronous left ventricular activation. Several criteria have been proposed, but not fully validated, to confirm LBp during implantation of pacing lead. Hypothesis: We hypothesized that higher frequency content of the paced QRS complex may show predictive value of successful LBp. Methods: We evaluated 84 patients with ejection fraction &gt;50%, who underwent LBB lead placement (n=42) using ≥1 current criteria and right ventricular midseptal (RVsp) lead placement (n=42) from 2000-22. Time frequency analysis (Matlab) was used to determine frequency content of paced QRS complex. Centroid Frequency (CF), which is the weighted average QRS frequency, was calculated. Unpaired t-test and Chi Square test were used for continuous and categorical variables, respectively. Multivariate analysis using logistic regression was used for variables with univariate p&lt;0.20. Variables with significant multivariate comparison (p&lt;0.05) underwent receiver operator curve analysis. Sensitivity and specificity for a CF ≥7.0 Hz for LBp was determined. Results: Baseline clinical characteristics are listed in Table 1. Patients in RVsp group had longer paced QRS duration (155.6 ± 28.0 vs 127.1 ± 17.2, p&lt;0.002) compared to LBp group. Of all ECG leads, V2 gave greatest difference, with CF of LBp group at 8.8 ± 1.6 Hz vs 5.7 ± 0.7 Hz of RVsp group (fig 1). This difference was significant by both univariate (p&lt;0.003) and multivariate (p&lt;0.010) analysis. Predictive value of CF for successful LBB pacing in lead V2 was highest with an AUC of 0.98. Sensitivity and specificity were 88.1% and 97.6%, respectively. Conclusions: Spectral analysis predicts successful LBp with higher frequency content when compared to RVsp pacing. Given the limitations to the current criteria to confirm LBp, intraprocedural use of frequency content analysis of the paced QRS complex in patients may prove a useful means of identifying LBB capture
Abstract 13288: Relationship Between the Detection of Atrial Fibrillation, Race and Complication Rate
Authors: Gauri Misra, Nick Prinz, Caroline Cotton, Randall Moorman, Oliver Monfredi
Journal: Circulation (2022)

Earlier work at our institution has shown that identification and treatment of atrial fibrillation (AF) is suboptimal in hospitalized patients. We set out to better characterize delays in the detection and management of AF, and to investigate their consequences We conducted a retrospective review of 425 consecutive clinically significant AF events (episodes lasting &gt;5 mins) generated by automated algorithmic continuous telemetry analysis between 12/25/20 and 9/21/21 for patients admitted to the cardiology floor of UVA Medical Center. Time of onset/duration of episodes were automatically recorded, and detailed chart review was performed. AF events in patients that generated clinical responses were significantly longer (median 2850 secs (SD 3962 secs; n=95)) than events in patients whose event was not identified by care teams (median 480 (SD 9280 secs; n=152), p &lt;.01). In patients who were clinically identified, the median delay to identification was 483 mins (SD 692 mins; n=95). Patients who had AF events identified by clinical care teams and received intervention (anticoagulation, rate limiting medication, anti-arrhythmic, IV fluid bolus or electrical cardioversion) within 60 minutes of the onset of the event had lower rates of subsequent AF-related complications (MI, stroke, heart failure or escalation of care) - those who received intervention within 60 minutes had subsequent AF-related complication rates of 10%, while who were intervened upon after 60 minutes had complication rates of 18%. Non-white patients were more likely to have their incident AF event missed by clinical care teams - among those patients who had AF identified, 85% were white, and 15% were non-white, while among patients who had AF but were not identified, 70% were white and 30% were non-white (p-value &lt;0.05). In conclusion, incident AF detection and management in our hospital is markedly delayed, and these delays are consequential in terms of risk of subsequent AF-related complications. Likelihood of an AF event leading to clinical recognition also appears to depend on race. Our future work will investigate the use of automated clinical team alerting of incident AF events to shorten times to AF detection and management, and effects of that on AF related complications and outcomes.
Abstract 13537: The Difference Between Cystatin C- and Creatinine-Based Kidney Function Assessment is Associated With Clinical Outcomes, Quality of Life and Frailty in Patients With Heart Failure and Reduced Ejection Fraction: Insights From PARADIGM-HF
Authors: Alberto Pinsino, Matthew R Carey, Husain A Syed, Douglas L Jennings, Sumit Mohan, Koji Takeda, Yoshifumi Naka, Gabriel T Sayer, Nir Uriel, Ryan T Demmer, Paolo C Colombo, Melana Yuzefpolskaya
Journal: Circulation (2022)

Introduction: Discrepancies between cystatin C (CysC)- and serum creatinine (sCr)- estimated glomerular filtration rate (eGFR) may reflect sarcopenia and malnutrition. Among pts with heart failure and reduced ejection fraction (HFrEF) enrolled in PARADIGM-HF (Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF), we investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes, quality of life (QoL) and frailty. Methods: Intra-individual differences between eGFRCysC and eGFRsCr (eGFRdiff) were calculated at randomization (n=1,970) and 8-month follow-up (n=1,631). Study outcomes included a composite of cardiovascular (CV) mortality or HF admission, and, separately, CV and all-cause mortality, worsening kidney function, poor QoL and frailty. Worsening HF was defined as outpatient intensification of HF therapy, emergency department visit or HF admission between randomization and 8-month follow-up. Results: At randomization, eGFRdiff was &gt;10 and &lt;-10 ml/min/1.73 m 2 in 25 and 36% of the pts, respectively. More negative values of eGFRdiff were associated with worse outcomes (adjusted hazard ratio per 1-standard deviation [SD]: CV mortality or HF admission 1.20, p=.003; CV mortality 1.37, p&lt;.001; all-cause mortality 1.42, p&lt;.001; worsening kidney function 1.30, p=.066). For each 1-SD decrease in eGFRdiff, the prevalence of poor QoL and frailty increased by 28% and 19%, respectively (p ≤.003). Pts with worsening HF had more marked decline in eGFRCysC than eGFRsCr. As a result, worsening HF was associated with a change in 8-month eGFRdiff by -4.7 ml/min/1.73 m 2 ( Figure ). Conclusions: In HFrEF pts, discrepancies between eGFRCysC and eGFRsCr are common and are associated with clinical outcomes, QoL and frailty. In pts with worsening HF, sCr may underestimate decline in kidney function due to changes in muscle mass and diet.
Abstract 13371: Beneficial Effects of Growth Hormone Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure With Preserved Ejection Fraction
Authors: Rosemeire M Kanashiro-Takeuchi, Lauro M Takeuchi, Raul A Dulce, Katarzyna Kazmierczak, Wayne Balkan, Renzhi Cai, Andrew Schally, Joshua M Hare
Journal: Circulation (2022)

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need due to its complex pathophysiology and lack of effective therapies. We previously showed that growth hormone-releasing hormone (GHRH)-agonists improve the phenotype of models of HF with reduced EF (HFrEF) and cardiorenal models of HFpEF. Hypothesis: We tested the hypothesis that the GHRH-agonist, MR-356 mitigates/reverses the cardio-metabolic HFpEF phenotype. Methods: C57BL6N mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of the HFD+L-NAME diet, animals were randomized to receive daily injections of MR-356 or placebo for 4-weeks. Control animals received no HFD+L-NAME or agonist treatment. Cardiac performance was assessed by echocardiography and hemodynamic measurements. Blood pressure, glucose tolerance, and exercise capacity, as well as cardiac hypertrophy, fibrosis, capillary density, and lung congestion were evaluated. Results: After 5 weeks of HFD+L-NAME diet, the placebo group showed impaired diastolic function (increased E/E’ratio, EDPVR, end-diastolic pressure), glucose intolerance and reduced global longitudinal strain and exercise capacity (p&lt;0.05). MR-356 treatment improved all of these parameters (p&lt;0.05). Cardiac hypertrophy, fibrosis, and capillary rarefaction in the placebo group (p&lt;0.05) were completely restored by MR-356 (p&lt;0.05). The increased expression of cardiac pro-BNP, and inducible nitric oxide synthase (iNOS) in the placebo group (p&lt;0.05) was brought to normal levels by MR-356 (p&lt;0.05). Hypophosphorylation of the titin isoforms in the placebo group (p&lt;0.05) was attenuated in the MR-356 group. Conclusions: Our data show the unique potential of MR-356 to treat several HFpEF-like features including diastolic dysfunction, cardiac hypertrophy, fibrosis, and exercise intolerance, suggesting that MR-356 reduces myocardial stress associated with metabolic inflammation in HFpEF. Thus, GHRH-agonists may be an effective therapeutic strategy for the treatment of the cardiometabolic HFpEF phenotype.
Abstract 13188: Co-Translational Profiling in the Cardiac Endothelium During the Development of Sepsis
Authors: Paul Goldspink, Chad M Warren, Bhairavi Swaminathan, Paulina Langa, Stephanie Niemczyk, Beata M Wolska, Jan Kitajewski, Pieter deTombe, R John Solaro
Journal: Circulation (2022)

Introduction: The production of functional proteins is a multistep process whereby key maturation and regulatory processes occur co-translationally by coupling mRNA translation and nascent polypeptide chain maturation on the ribosome. However, limited data exist regarding co-translational regulation in the cells of the intact cardiovascular system. To overcome this limitation, we adapted the translating ribosome affinity purification (TRAP) approach using the HA-tagged ribosomal protein L22 reporter mouse (RiboTag) crossed with an inducible endothelial-specific Cdh5creERT2 mouse ( RiboTag EC ). Hypothesis: We hypothesized this model would permit the simultaneous immunoprecipitation (IP) of mRNA and nascent proteins for RNAseq and proteomic analysis from the coronary endothelium. Methods: Mice were injected with E. coli lipopolysaccharide (LPS) (6mg/Kg, i.p. 12 hours) to induce sepsis and perturb endothelial cell function. Hearts were homogenized, a small amount (~10%) was used for RNA-Seq and proteomics input controls (IN), and the remainder was used to IP ribosomal bound polyA+ mRNA and nascent proteins. Eluted proteins were digested, labeled with isobaric tags for quantification, and analyzed by MS3 with a Thermo Scientific Fusion Lumos Orbitrap. Results: Principal components analysis of the RNAseq data showed clear separation of the IP (endothelial cells) and IN (whole heart) transcriptomes between control and LPS groups. Transcripts characteristic of endothelial cells (EC) were enriched, whereas markers characteristic of cardiomyocytes, fibroblasts, and smooth muscle cells were depleted. Overall, &gt;7000 proteins were identified, and initial analysis showed similar depletion and enrichment of proteins in the control and LPS hearts. Alignment of transcript and protein datasets was used for bioinformatic analysis. A hierarchical view of one of the top networks in which concordant expression of both EC transcripts and proteins identified interferon-gamma (IFNG) as an upstream signal in the pathogenesis of sepsis. Conclusions: Our “functional translatome” approach is a new discovery platform for a deeper predictive analysis of functionally relevant signaling networks and disease pathways in the intact cardiovascular system.
Abstract 13750: Substernal Extravascular Implantable Cardioverter-Defibrillator System Infection in Large Animals
Authors: Amy Thompson, Melissa Christie, Linnea R Lentz
Journal: Circulation (2022)

Background: The Extravascular ICD (EV ICD) with substernal lead placement may provide clinical advantages to transvenous and subcutaneous systems. An understanding of substernal infection manifestation and treatment is required. Methods: The EV ICD system was implanted in 13 large animals (canine, porcine, ovine), and porcine were co-implanted with a transvenous CRT-D system. Animals were monitored for clinical presentation of infection over 12-18 weeks of follow-up, and cultures were collected to confirm infection. Treatment was bifurcated, with some animals receiving antibiotics while EV ICD leads remained in situ , and other animals treated with system removal and antibiotics. Histopathology was conducted at the end of study. Results: Five infections were confirmed over the course of study, 4 of which involved infection of the EV ICD system and 1 of which involved infection of only the concomitantly implanted CRT-D system without infection of the EV ICD system. Two of the EV ICD-related infections were treated with system removal and antibiotic course, and both infections resolved. Two additional EV ICD-related infections were treated with antibiotics alone without explant of the EV ICD leads; histology showed that neither infection resolved. The transvenous CRT-D system infection progressed to septicemia and endocarditis, requiring early study end. No EV ICD-related infection progressed to blood stream infection, and the sternal bone did not become infected when infection was present in the substernal tissues. Conclusions: Study findings suggest that EV ICD-related infections are treatable with system removal and antibiotic therapy.
Abstract 13383: Is Genotype Negative Hypertrophic Cardiomyopathy Really Benign? The Increased Risk of Sudden Death and Advanced Heart Failure in the Absence of Pathogenic Sarcomere Mutations
Authors: Jiri Bonaventura, Michael T Chin, Barry J Maron, Martin S Maron, Ethan J Rowin
Journal: Circulation (2022)

Introduction: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the genotype-phenotype correlations have not been completely resolved. Patients lacking a pathogenic variant are presumed to have a better prognosis than patients with sarcomeric pathogenic mutations. Aim: We sought to assess the relationship between the genotype status and the adverse clinical events. Methods: Consecutive patients with HCM underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation were considered genotype negative (G-). Patients were followed for 5.2 ±4.9 years for outcomes. Sudden death (SD) events included out-of-hospital cardiac arrests, appropriate ICD interventions, and HCM-related death. Results: Of 988 HCM patients, 212 (21%) were G+, while 776 (79%) were G -. As compared to G-, G+ HCM patients were younger (45 ± 14 vs. 53 ± 13 years), had more extensive LV hypertrophy (maximum wall thickness: 19.6 ± 5 mm vs. 18.4 ± 4 mm, p&lt;0.001), and with no difference in the presence of LVOT obstruction (59% vs. 66%, p=0.06). Despite G- status, 3% of G- patients had extensive scarring on cardiac MRI (≥15% of LV mass; no different from G+, p=0.54). Over follow-up, 66 patients had SD events. While SD events were more common in G+ patients (11.3% vs. 5.4%, p=0.002), the majority of SD events occurred in G- patients (64%). Similarly, end-stage HCM developed 54 patients, more commonly in G+ (9.0% vs. 4.5%, p=0.01), but with majority of events in G- patients (65%). Conclusion: Contrary to certain prevailing views, in this large consecutive genotyped HCM cohort, sarcomere genotype-negative patients (representing a distinctive majority) did not express an entirely benign prognosis. In fact, nearly two-thirds of SD events and end-stage HF progression occurred in G- HCM patients, albeit at somewhat lower rates than in G+ patients. These data do not support that genotype should not be included as a risk marker of adverse arrhythmic and advanced heart failure events.
Abstract 13311: Risk of Ventricular Tachycardia and Sudden Cardiac Arrest Associated With Drugs Known to Cause Torsades De Pointes in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Chien-Yu Huang, Brian R Overholser, Kevin M Sowinski, Heather A Jaynes, Richard KOVACS, James E Tisdale
Journal: Circulation (2022)

Introduction: Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced proarrhythmia. It is unknown whether patients with HF with preserved ejection fraction (HFpEF) are also at increased risk. Hypothesis: The risk of drug-associated ventricular tachycardia (VT) and sudden cardiac arrest (SCA) is increased in patients with HFpEF. Methods: Using Medicare enrollment in fee-for-service medical and pharmacy benefits (2014 to 2016) and ICD-9/10 codes, we identified patients taking drugs known to cause torsades de pointes (TdP drugs; www.crediblemeds.org) and non-TdP drug users among three groups: HFrEF (n=31,422), HFpEF (n=40,012), and no HF (n=633,558). Multinomial propensity score-matching was performed to minimize baseline differences in covariates (patient demographics, comorbidities, health care utilization and drug history). Cochran-Mantel-Haenszel statistics and standardized differences were used to compare baseline characteristics. A generalized Cox proportional hazards model was used to estimate hazard ratios (HRs) and test the association of VT and SCA among TdP drug users with HFpEF, HFrEF, and no HF. Results: Of 23,910 TdP drug users with HFrEF, VT and SCA occurred in 4,263 (17.8%) and 493 (2.1%) patients, respectively. In comparison, among 31,359 TdP drug users with HFpEF, VT and SCA occurred in 1,570 (5.0%) and 340 (1.1%) patients. VT and SCA occurred in 3,154 (0.8%) and 528 (0.1%) of 384,824 TdP drug users without HF. The overall risk of both VT and SCA was increased in patients with HFrEF and in those with HFpEF (Table). The risk of VT associated with TdP drugs was increased across the overall population. Use of TdP drugs significantly increased the risk of VT and SCA in patients with HFrEF, but not in patients with HFpEF. Conclusions: The risk of VT and SCA associated with drugs known to cause TdP was increased in patients with HFrEF but not in those with HFpEF.
Abstract 14629: Predictive Model Testing for Life-Sustaining Treatment Decisions at the End-of-Life: Applying Machine Learning Methods
Authors: Minjeong An, Hoi-Jeong Lim, Seongkum Heo, Jongho Kim, JinShil Kim
Journal: Circulation (2022)

Introduction: Predictive models of factors affecting decisions about life-sustaining treatments (LSTs) have been frequently examined, but the accuracy and precision of those models remain elusive. Machine learning algorithms (MLAs) may help identify the best model in terms of its performance measures. Objectives: To determine the best MLA to predict LST preferences (cardiopulmonary resuscitation [CPR], ventilation support, and hemodialysis, and hospice care). Methods: In this secondary analysis, three MLA-based prediction models of LST preferences, including seven known predictors, were developed based on random forest (RF), logistics regression (LR), and linear support vector machine (SVM), and were evaluated by a five-fold validation set comprising accuracy, precision, area under the receiver operating characteristic curve, recall, and F1 score. Results: Among 375 adults with malignancy or non-malignancy diseases or healthy adults, 23.2% preferred CPR, 17.9% ventilation support, 19.2% hemodialysis, and 60.8% hospice care. Compared to RF and LR, SVM was the most accurate and precise model to predict each preference of CPR (0.78 vs. 0.85; 0.15-0.44 vs. 0.75, respectively), ventilation support (0.84 vs. 0.88; 0.00-0.10 vs. 0.89, respectively), hemodialysis (0.82 vs. 0.84; 0.33-0.54 vs. 0.69, respectively), and hospice care (0.64-0.68 vs. 0.85; 0.65-0.70 vs. 0.84, respectively). In the models, age, attitudes toward advance directives, and susceptibility to end-of-life care were reported as common predictors with relatively high importance on LST preferences (Table 1). Conclusions: SVM was the best model in identifying predictors of LST preferences in people with or without chronic diseases. In addition, the findings suggest important targets of interventions, including attitudes toward advance directives, and susceptibility to end-of-life care, to assist people to make the best decisions for their future medical care.